Stressors

Taxonomic Applicability

Life Stages

Sex Applicability

Key Event Description

TH signalling controls a number of major anatomical processes in development that if altered will lead to permanently abnormal brain morphology. These processes include differentiation of neurons and glia from progenitor cells, neuronal migration, and myelination of axonal processes. The evidence supporting a role of TH in these neurodevelopmental processes is strong. Evidence from human is primarily from studies of iodine-deficient children and children with congenital hypothyroidism (CH)(Zoeller and Rovet, 2004). Animal models using rats and mice, as well as in vitro studies, have provided ample evidence of TH control of these processes (Gilbert and Zoeller, 2010). Below are brief descriptions of the impact of TH insufficiency on two of these processes.

Altered Axonal Myelination: Nerve conduction is accelerated by the insulation formed by oligodendrocytes of the myelin sheath that surround axons of many nerve fibers. Reduced size and altered composition of the white matter tracts throughout the brain, the most prominent of which is the corpus callosusm, are hallmarks of severe developmental hypothyroidism (Berbel et al., 1993, 1994; Ferreira et al., 2004; Gravel and Hawkes, 1990; Ibarrola and Rodriguez-Pena, 1997; Schnoover et al., 2005). In addition, more subtle abnormalities have been described in white matter tracks including corpus callosum and anterior commissure following more modest reductions in circulating levels of TH in the neonatal period (Sharlin et al., 2008).

How It Is Measured or Detected

Data in support of this key event have been collected using a wide variety of standard biochemical, histological and anatomical methods (eg., morphometrics, immunohistochemical staining, in situ hybridation) and imaging procedures. Many of methods applied to reveal anatomical abnormalities are routine neurohistopatholgical procedures similar to those recommended in EPA and OECD developmental neurotoxicity guidelines. Subtle changes in cytoarchitecure such as seen in the neocortex depend on more specialized birth dating procedures and staining techniques. Some alterations in brain structure are transient in nature and depend on appropriate timing for detection.

Domain of Applicability

The majority of the evidence supporting this KE comes from rodent studies. However, amphibians display vast structural remodelling during metamorphosis that is TH-dependent and share common TH signaling pathways with rat brain development.